Vascular remodeling in response to injury and in atherosclerosis is believed to be mediated by different mechanisms. Although platelet-monocyte-vascular cell interactions and neointima formation occur in both; inflammatory and thrombotic lesions after injury are not seen in animals. Surprisingly, we found such inflammatory atherosclerotic-like lesions post-angioplasty in rats treated perivascularly with neuropeptide Y (NPY), a sympathetic co-transmitter and vascular mitogen. While studying NPY and its receptors (Rs) in restenosis /atherosclerosis, we discovered that C57/BL mice, also used for pro- atherosclerotic ApoE-/- - do not express NPY in megakaryocytes (MK)/platelets and form mild or no lesions in response to angioplasty (neointima) and atherosclerosis (intimal xanthomas), whereas strains that do (all rats, Sv129, FVB) - develop significant lesions. Stress amplified post-angioplasty lesions and in platelet NPY-expressing rats advanced them into macrophage-rich, thrombotic atherosclerotic-like lesions. This was paralleled by a stress-induced increase in MK turnover and up-regulation of NPY expression in MK/platelets, mediated by sympathetic, NPY-ergic activation of MKs. The hypothesis that platelet NPY, at certain threshold concentrations, triggers the inflammatory cascade was formed when transfer of NPY-/- platelets into NPY+/+ mice, or Y1R antagonist completely prevented post-angioplasty macrophage transmigration and neointima formation. These intriguing data led us to propose that stress, via platelet NPY, amplifies vascular atherosclerotic remodeling by stimulating proinflammatory platelet-immune- endothelial-vascular interactions (Aim 1-3) and upregulating MK/platelet NPY expression (Aim 4). This is mediated by vascular and monocytic Y1R (Aim 1/3A), and antagonized by endothelial and macrophage-derived DPPIV/cd26 (Aim 1/3B), which inactivates NPY- Y1R-mediated and monocytic chemoattractant activities of RANTES and SDF-1 (Aim 1B). In vitro, platelet-monocyte-endothelial interactions will be studied in human and murine cells derived from mice with or without NPY, Y1R, DPPIV/cd26, or P-selectin, and in vivo, in the same mice after angioplasty with or without stress and platelet transfer (Aim 5). The critical role of monocytic Y1Rs in the platelet NPY-triggered inflammatory cascade will be tested with a conditional, monocyte-specific Y1R deletion (Y1R lox/lox crossed with Cre-Lyzs ).This will be the first time that mechanisms of actions of chronic stress on atherosclerotic remodeling will be studied at the cellular-molecular level.